Many polar drugs and prodrugs have a limited shelf-life not due to a loss in potency in the compounds them selves but due to the nucleation/precipitation of their degradants which are poorly water soluble. The impact of the poorly water soluble degradants on the shelf-life of drugs and prodrugs can be demonstrated by the following example. A drug formulated at 10 mg/ml which has a degradant with a solubility of 10 .mu.g/ml (in parent drug molar equivalents) can only tolerate a 0.1% degradation before the degradant may precipitate from solution and render the drug unusable.
Since the presence of particulate species is undesirable, particularly with injectable drugs and prodrugs, the parent drug or prodrug must have very good chemical stability to provide a desired two-year shelf-life. Because of a lack of stability, it is not possible to obtain a long, minimum of two years, shelf-life with many of the water soluble prodrugs of insoluble drugs or with water soluble drugs which have insoluble degradants. The shelf-life of water-soluble prodrugs or drugs is further complicated and shortened if there is any degradant present in the original product as a contaminant.
One example of a water soluble prodrug of a water insoluble drug is fosphenytoin. Fosphenytoin has been developed as a water soluble prodrug of the active drug compound phenytoin (U.S. Pat. No. 4,925,860; Varia et al., J. Pharm. Sci. 73, 1074-1080, 1984). When fosphenytoin is formulated as fosphenytoin dihydrate at a concentration of 80.6 mg/ml or as anhydrous fosphenytoin at a concentration of 75 mg/ml, it decomposes at pH values less than 8.0 primarily to phenytoin, which has an intrinsic aqueous solubility of less than 25 .mu.g/ml. Because of the poor aqueous solubility of phenytoin, at pH values of either 7.4 or 8.0 in 0.02 M Tris buffer, only about 0.1% degradation of fosphenytoin can be tolerated before nucleation of phenytoin occurs.
To overcome the solubility problems of phenytoin, the prodrug fosphenytoin is generally formulated at a high pH of 8.5 (U.S. Pat. No. 4,925,860). However, fosphenytoin is actually more stable at a lower pH. Because of the instability of fosphenytoin at high pH values, it is only possible to obtain a shelf-life of two years for the prodrug product by refrigeration. In addition, the high pH needed is less physiologically acceptable and the degradants are more complex in structure, raising the issue of toxicity from degradants.
Numerous prior art references, including Okimoto et al., Pharm. Res. 13:256-264; Loftsson and Brewster, J. Pharm. Sci. 85:1017-1025; and U.S. Pat. No. 5,134,127, teach compositions of cyclodextrins with drugs. These compositions of the prior art teach at least equimolar amounts of cyclodextrin and drug for the purpose of solubilizing the drug. To our knowledge, the issue of solubilization of poorly soluble degradants in the presence of high concentrations of parent drug has not been addressed either in the scientific or patent literature.